Gliomas are the most common and deadly malignant tumors of the central nervous system. Glioma cells diffusely infiltrate adjacent and often distant brain structures, a property which renders them largely incurable. To effectively control gliomas, the mechanisms underlying tumor cell invasion and progression must be determined and targeted with novel therapies. However, the signals that govern infiltration are largely unidentified. Mouse models and human tissue culture models have provided valuable insights into the roles of known genetic alterations in glioma, but because of the difficulty in carrying out forward genetic screens, they have not been widely used to discover new genes involved in glioma pathogenesis. The goal of this project is to create a model of glioma in the fruit fly Drosophila for the purpose of carrying out large- scale genetic screens to identify genes involved in glioma invasion and progression. Drosophila glia share many properties with mammalian glia, including the display of infiltrative, glioma-like tumor phenotypes upon co-activation of the EGFR-Ras and PIS kinase signaling pathways. In this project, candidate loci implicated in human gliogenesis will be evaluated and novel regulators of EGFR-Ras/PI3 kinase-induced invasiveness will be searched for. Drosophila orthologs of genes known to be upregulated in glioma, but whose roles in pathogenesis are unknown, will be misexpressed specifically in glial cells and assayed for glioma-like phenotypes. A screen for mutations that enhance or suppress the glioma-like invasive phenotype upon EGFR-Ras and PIS kinase pathway activation will be carried out and the identity of the corresponding genes will be established. The genes identified in these screens will represent excellent candidates for genes directly involved in pathogenesis. Relevance: These studies are expected to provide key insights into glioma pathogenesis, including the identity of genes involved in tumor cell migration and invasiveness. The products of these genes may represent excellent targets for therapeutics. [unreadable] [unreadable] [unreadable] [unreadable]